1. Field of the Invention
The present invention relates to a new class of compounds having a variable spectrum of activities for capsaicin-like responses, compositions thereof, processes for preparing the same, and uses thereof.
2. Description of Related Art
Resiniferatoxin (RTX) is an extremely irritant diterpene present in the latex of several members of the genus Euphorbia (Hergenhahn et al., Tetrahedredron Lett., Vol. 19, p. 1595 (1975); Schmidt et al., Phytochemistry, Vol. 15, p. 1778 (1976)). It was isolated based on its extraordinary activity in the mouse ear erythema assay (Hergenhahn et al., Tetrahedron Lett., Vol. 19, p. 1595 (1975)) in which it was found to be 1000-fold more potent than the most active of the typical phorbol esters, phorbol 12-myristate 13-acetate (Hecker, Carcinogenesis, Vol. 2, p. 11, Raven Press, New York (1978); Adolph et al., J. Nat. Prod., Vol. 45, p. 347 (1982)). Except for its irritancy, RTX failed to induce typical phorbol ester effects (e.g. promoting activity or activation of EB virus (zur Hausen et al., Proc. Natl. Acad. Sci. USA, Vol. 76, p. 782 (1979)), release of fibronectin (Driedger et al., Cancer Res., Vol. 40, p. 1400 (1980a)), competition for phorbol ester binding to protein kinase C (Driedger et al., Proc. Natl. Acad. Sci. USA, Vol. 77, p. 567 (1980b)), indicating that it exerted its irritancy via a different pathway.
RTX differs from those resiniferonol derivatives which are tumor promoting in that it is esterified with homovanillic acid at the C20 position. Structure-activity analysis had indicated that this substituent is critical for its acute irritant activity (Adolph et al., J. Nat. Prod., Vol. 45, p. 347 (1982); Schmidt et al., Inflammation, Vol. 3, p. 273 (1979)), whereas a free C20 hydroxyl is required for the promoting activity of typical phorbol esters (Hecker, Carcinogenesis, Vol. 2, p. 11, Raven Press, New York (1978)). Strikingly, a homovanillyl substituent also plays an essential role in determining the pungency of capsaicin, the major irritant constituent in red pepper and other species of the genus Capsicum (Jancso, Pharmacology of Pain, Vol. 9, p. 33, Permamon Press, Oxford (1968); Szolcsanyi and Jancso-Gabor, Arzneim.-Forsch. (Drug Res.), Vol. 25, p. 1877 (1975)).
Recently, it has been demonstrated that RTX acts as an ultrapotent analog of capsaicin (Szallasi et al., Neuroscience (in press, 1989); RTX excites and then desensitizes polymodal nociceptor neurons. These sensory neurons are located in the dorsal root and Gasser ganglia. They transmit perception of pain to the central nervous system and mediate the release of inflammatory neurotransmitters (e.g. substance P) in the periphery (Buck et al., Pharmacol. Rev., Vol. 38, p. 179 (1986)). RTX was 3-4 orders of magnitude more potent compared to capsaicin, the most active known congener of its class (Szallasi et al., Neuroscience (in press, 1989)).
These results raised the possibility that other 20-homovanillyl esters of diterpenes might also be potent sensory neuromodulator agents. Given the renewed interest in the mechanism of action of capsaicin (Marsch et al., Neuroscience, Vol. 23, p. 275 (1987); Wood et al., J. Neuroscience, Vol. 8, p. 3208 (1988)) and its possible therapeutical implications (Geppetti et al., Br. J. Pharmacol., Vol. 93, p. 509 (1988); Levine et al., J. Neuroscience, Vol. 6, p. 3423 (1986)), the structure-activity analysis of such diterpenes might provide useful information on the requirements for interaction at the postulated capsaicin receptor (Szolcsanyi and Jancso-Gabor, Arzneim.-Forsch. (Drug Res.), Vol. 25, p. 1877 (1975)). Moreover, the compounds might provide further tools for dissecting subclasses of capsaicin responses, as was strongly implied by the differential activity of RTX (Szallasi et al., Neuroscience (in press, 1989)).
In the present study, the potencies of two homovanillyl diterpene derivatives of the new class of claimed compounds are examined, 12-deoxyphorbol 13-phenylacetate 20-homovanillate and mezerein 20-homovanillate for mimicking RTX. The structure of resiniferatoxin and its analogs along with Tinyatoxin are shown below. ##STR1## Activities are compared with those for the parent diterpenes, and all compounds are also examined to determine their binding affinities for protein kinase C.